Evolution of cortical neurons supporting human cognition
Authors: A.A. Galakhova, S. Hunt, R. Wilbers, D.B. Heyer, C.P.J. de Kock, H.D. Mansvelder, N.A. Goriounova
Journal: Trends in Cognitive Sciences (2022)

Cortical expansion in humans might be driven by changes in neuronal properties and connectivity rather than sheer increase in neuronal numbers.Recent breakthroughs in large-scale transcriptomic analyses of cortical neurons make it now possible to identify the genetic signature of neuron types and compare neuronal properties across species.Human upper cortical layers contain neurons with large and complex dendrites that allow a single human neuron to perform computations similar to a multilayered network.Strong and reliable synapses that recover quickly from synaptic activity, and fast signaling properties, help these neurons efficiently process information.Several neuronal features of human neurons, such as dendritic size and complexity and fast signaling properties, also associate with cognitive ability in human individuals, supporting the link between neurons and cognitive function not only between but also within species. Human cognitive abilities are generally thought to arise from cortical expansion over the course of human brain evolution. In addition to increased neuron numbers, this cortical expansion might be driven by adaptations in the properties of single neurons and their local circuits. We review recent findings on the distinct structural, functional, and transcriptomic features of human cortical neurons and their organization in cortical microstructure. We focus on the supragranular cortical layers, which showed the most prominent expansion during human brain evolution, and the properties of their principal cells: pyramidal neurons. We argue that the evolutionary adaptations in neuronal features that accompany the expansion of the human cortex partially underlie interindividual variability in human cognitive abilities. Human cognitive abilities are generally thought to arise from cortical expansion over the course of human brain evolution. In addition to increased neuron numbers, this cortical expansion might be driven by adaptations in the properties of single neurons and their local circuits. We review recent findings on the distinct structural, functional, and transcriptomic features of human cortical neurons and their organization in cortical microstructure. We focus on the supragranular cortical layers, which showed the most prominent expansion during human brain evolution, and the properties of their principal cells: pyramidal neurons. We argue that the evolutionary adaptations in neuronal features that accompany the expansion of the human cortex partially underlie interindividual variability in human cognitive abilities. Compared with other animals, human cognition clearly stands out. Many species can display very intelligent behavior, typically tuned to their ecological niche. However, human brains are capable of developing unique cognitive skills (e.g., sharing and storing information through symbolic language), without which human civilization would not be possible. For thousands of years, one of the most fundamental questions in philosophy and neuroscience has been the biological origin of human intelligence. What neurobiological principles underlie the cognitive abilities of the human species? A major development in the evolution of the mammalian brain is the immense expansion of the neocortex [1.DeFelipe J. The evolution of the brain, the human nature of cortical circuits, and intellectual creativity.Front. Neuroanat. 2011; 5: 29Crossref PubMed Scopus (307) Google Scholar]. The neocortex supports the higher cognitive functions that characterize humans. Relative to the total brain size, the human cerebral cortex is the largest among mammals, its grey and white matter occupies 75–82% of the entire brain mass or volume [2.Herculano-Houzel S. 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However, compared with other primates, the increase in both brain size and the number of neurons in humans is 'remarkable, yet not extraordinary' [2.Herculano-Houzel S. The remarkable, yet not extraordinary, human brain as a scaled-up primate brain and its associated cost.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: 10661-10668Crossref PubMed Scopus (363) Google Scholar] and the key to the puzzle of human cognition should not be sought solely in the overall brain or cortical anatomy. In fact, the human brain has just the number of neurons that would be expected for a primate brain of the same size [2.Herculano-Houzel S. The remarkable, yet not extraordinary, human brain as a scaled-up primate brain and its associated cost.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: 10661-10668Crossref PubMed Scopus (363) Google Scholar]. 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The overall result of this multiscale evolutionary process is not only increased cortical volume but increased diversity and complexity in the structure and function of cortical neurons and their synaptic connections. Thus, the speed and efficiency with which we accomplish cognitive tasks might be rooted deeper in the hierarchy of brain structure and arise from the characteristics of its basic elements: cortical neurons [15.Dorus S. et al.Accelerated evolution of nervous system genes in the origin of Homo sapiens.Cell. 2004; 119: 1027-1040Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar, 16.Goriounova N.A. et al.Large and fast human pyramidal neurons associate with intelligence.eLife. 2018; 7e41714Crossref PubMed Scopus (63) Google Scholar, 17.Lee K. et al.Human in vitro systems for examining synaptic function and plasticity in the brain.J. Neurophysiol. 2020; 123: 945-965Crossref PubMed Scopus (7) Google Scholar, 18.Hill R.S. Walsh C.A. 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By comparing human cortical neurons with those of other species, evolutionarily conserved neuronal cell types and features can be distinguished from those unique to humans. In this review, we discuss the evolution of the human brain from the vantage point of single cortical neurons and their local circuits. We attempt to answer how the evolutionary increase in brain size and complexity is linked to adaptations in the structure and function of human cortical neurons. We put forward the hypothesis that neuronal properties may partially explain the observed gap in mental ability between humans and other species and provide an overview of the recent evidence for this. We focus primarily on the adult pyramidal neurons, the most abundant cortical neuron type, but acknowledge that other cell types and neurotransmitter systems [22.Berto S. et al.Accelerated evolution of oligodendrocytes in the human brain.Proc. Natl. Acad. Sci. U. S. 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Timing as a mechanism of development and evolution in the cerebral cortex.Brain Behav. Evol. 2022; 97: 8-32Google Scholar]. Finally, the focus of our review is on the pyramidal neurons of supragranular layers, as the morpho-electric properties of these neurons are more extensively studied in human cortex compared with deeper layers. Comparing cortical structure across multiple orders of mammalian species [27.Butti C. et al.The neocortex of cetartiodactyls: I. A comparative Golgi analysis of neuronal morphology in the bottlenose dolphin (Tursiops truncatus), the minke whale (Balaenoptera acutorostrata), and the humpback whale (Megaptera novaeangliae).Brain Struct. Funct. 2015; 220: 3339-3368Crossref PubMed Scopus (27) Google Scholar, 28.Jacobs B. et al.Comparative morphology of gigantopyramidal neurons in primary motor cortex across mammals.J. Comp. 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Towards a unified scheme of cortical lamination for primary visual cortex across primates: insights from NeuN and VGLUT2 immunoreactivity.Front. Neuroanat. 2014; 8: 81Crossref PubMed Scopus (41) Google Scholar,32.Semendeferi K. et al.Spatial organization of neurons in the frontal pole sets humans apart from great apes.Cereb. Cortex. 2011; 21: 1485-1497Crossref PubMed Scopus (157) Google Scholar]. Although the mammalian neocortex has a similar six-layered structure (Box 1), across the neocortex there are substantial variations in the thickness of these layers and overall cytoarchitectonic organization. This variation reflects the functional role of cortical areas [33.Elston G.N. Cortex, cognition and the cell: new insights into the pyramidal neuron and prefrontal function.Cereb. Cortex. 2003; 13: 1124-1138Crossref PubMed Scopus (329) Google Scholar,34.Elston G.N. Specialization of the neocortical pyramidal cell during primate evolution.in: Kass J.H. Evolution of Nervous Systems. 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From sensory to more integrative cortical areas, there is a gradient of increasingly thicker cortex [37.Wagstyl K. et al.Cortical thickness gradients in structural hierarchies.Neuroimage. 2015; 111: 241-250Crossref PubMed Scopus (104) Google Scholar] (supported mostly by layers 3 (L3) and 5 (L5), which contain large pyramidal neurons [38.Wagstyl K. et al.BigBrain 3D atlas of cortical layers: cortical and laminar thickness gradients diverge in sensory and motor cortices.PLoS Biol. 2020; 18e3000678Crossref PubMed Scopus (68) Google Scholar]), larger neurons with more complex dendritic arbors [39.Behav B. et al.The evolutions of large brain size in mammals: the "over-700-gram club quartet".Brain Behav. Evol. 2013; 82: 68-78Google Scholar,40.Elston G.N. Fujita I. Pyramidal cell development: postnatal spinogenesis, dendritic growth, axon growth, and electrophysiology.Front. Neuroanat. 2014; 8: 78Crossref PubMed Scopus (102) Google Scholar], and greater number of dendritic spines for synaptic contacts [41.Jacobs B. et al.Regional dendritic and spine variation in human cerebral cortex: a quantitative Golgi study.Cereb. Cortex. 2001; 11: 558-571Crossref PubMed Scopus (343) Google Scholar] (Figure 1). The larger pyramidal neuron size in larger brains across species is particularly pronounced in higher-order association areas [12.Elston G.N. et al.The pyramidal cell in cognition: a comparative study in human and monkey.J. Neurosci. 2001; 21: RC163Crossref PubMed Google Scholar,40.Elston G.N. Fujita I. Pyramidal cell development: postnatal spinogenesis, dendritic growth, axon growth, and electrophysiology.Front. Neuroanat. 2014; 8: 78Crossref PubMed Scopus (102) Google Scholar,42.Bianchi S. et al.Dendritic morphology of pyramidal neurons in the chimpanzee neocortex: regional specializations and comparison to humans.Cereb. Cortex. 2013; 23: 2429-2436Crossref PubMed Scopus (98) Google Scholar]. Even the gigantopyramidal Betz cells in primary motor cortex, although having a larger soma and covering a larger cortical volume in big cats, have the most complex dendrites and longest total dendritic length in primates [20.Bakken T.E. et al.Comparative cellular analysis of motor cortex in human, marmoset and mouse.Nature. 2021; 598: 111-119Crossref PubMed Scopus (143) Google Scholar,28.Jacobs B. et al.Comparative morphology of gigantopyramidal neurons in primary motor cortex across mammals.J. Comp. Neurol. 2018; 526: 496-536Google Scholar]. Yet, cortical synapse densities remain relatively constant, resulting in humans having the highest number of synapses per neuron [12.Elston G.N. et al.The pyramidal cell in cognition: a comparative study in human and monkey.J. Neurosci. 2001; 21: RC163Crossref PubMed Google Scholar,30.Sherwood C.C. et al.Invariant synapse density and neuronal connectivity scaling in primate neocortical evolution.Cereb. Cortex. 2020; 30: 5604-5615Crossref PubMed Scopus (13) Google Scholar,43.Benavides-Piccione R. et al.Cortical area and species differences in dendritic spine morphology.J. Neurocytol. 2002; 31: 337-346Crossref PubMed Scopus (138) Google Scholar].Box 1Cortical organization and cortical neuronsIn mammalian species, including humans, cortical neurons are arranged into a six-layered structure [1.DeFelipe J. The evolution of the brain, the human nature of cortical circuits, and intellectual creativity.Front. Neuroanat. 2011; 5: 29Crossref PubMed Scopus (307) Google Scholar,8.DeFelipe J. et al.Microstructure of the neocortex: comparative aspects.J. Neurocytol. 2002; 31: 299-316Crossref PubMed Scopus (480) Google Scholar,47.Mohan H. et al.Dendritic and axonal architecture of individual pyramidal neurons across layers of adult human neocortex.Cereb. Cortex. 2015; 25: 4839-4853Crossref PubMed Scopus (116) Google Scholar]. Cortical layers 2–6 (L2–L6) contain predominantly (70–80%) pyramidal neurons, the principal projection neurons of the cortex. They accumulate and integrate synaptic information on their vast dendrites and pass it on locally or to other cortical and subcortical areas through excitatory synapses. Although the principal load of information transmission lies on pyramidal neurons, their activity is strongly regulated and shaped by a diverse population of local inhibitory interneurons [8.DeFelipe J. et al.Microstructure of the neocortex: comparative aspects.J. Neurocytol. 2002; 31: 299-316Crossref PubMed Scopus (480) Google Scholar].The broad structural characteristics of pyramidal neurons are similar across species: these neurons consist of a pyramidal-shaped soma that gives rise to apical and basal dendrites. The apical dendrite is orientated towards the cortical surface and ends in a distal tuft, while basal dendrites extend radially towards deeper layers.The stereotypical organization of the cortex in a laminar structure has long tempted neuroscientists to derive generalized rules for connectivity. L1 contains mainly dendrites and axons of neurons from other layers and a sparse population of interneurons to regulate the inputs [101.Genescu I. Garel S. Being superficial: a developmental viewpoint on cortical layer 1 wiring.Curr. Opin. Neurobiol. 2021; 66: 125-134Crossref PubMed Scopus (13) Google Scholar]. Based on neuroanatomical and physiological evidence, the upper supragranular layers, L2/L3, are thought to be the place where most recurrent computation happens: L2/L3 pyramidal cells have many re-excitatory connections, preamplify information, and send it to pyramidal cells in deeper output L5/L6 [102.Shepherd G.M. The microcircuit concept applied to cortical evolution: from three-layer to six-layer cortex.Front. Neuroanat. 2011; 5: 30Crossref PubMed Scopus (76) Google Scholar]. L3 pyramidal cells are also the main source of the feedforward projections to other cortical areas and receive recurrent input from other local superficial and deep pyramidal cells. L5 pyramidal cells are part of both direct thalamocortical and cortico-cortical microcircuits and dictate output to subcortical structures [103.Takahashi N. et al.Active dendritic currents gate descending cortical outputs in perception.Nat. Neurosci. 2020; 23: 1277-1285Crossref PubMed Scopus (70) Google Scholar].Supragranular layers seem to play an especially important role in cortico-cortical connectivity in the human brain (see Figure 2 in main text). Relative to monkeys and other primates, in humans there is a progressive shift of the laminar origin of connections from deeper (L5/L6) to upper layers (L2/L3). The result is that within human cortex a larger proportion of cortico-cortical connections originate from the supragranular layers [44.Goulas A. et al.Cortical gradients and laminar projections in mammals.Trends Neurosci. 2018; 41: 775-788Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar]. These layers are also proportionately thicker in the human cortex compared with other primates [46.Hutsler J.J. et al.Comparative analysis of cortical layering and supragranular layer enlargement in rodent carnivore and primate species.Brain Res. 2005; 1052: 71-81Crossref PubMed Scopus (98) Google Scholar], supporting a more important role of these layers in the integration of cortical information. In mammalian species, including humans, cortical neurons are arranged into a six-layered structure [1.DeFelipe J. The evolution of the brain, the human nature of cortical circuits, and intellectual creativity.Front. Neuroanat. 2011; 5: 29Crossref PubMed Scopus (307) Google Scholar,8.DeFelipe J. et al.Microstructure of the neocortex: comparative aspects.J. Neurocytol. 2002; 31: 299-316Crossref PubMed Scopus (480) Google Scholar,47.Mohan H. et al.Dendritic and axonal architecture of individual pyramidal neurons across layers of adult human neocortex.Cereb. Cortex. 2015; 25: 4839-4853Crossref PubMed Scopus (116) Google Scholar]. Cortical layers 2–6 (L2–L6) contain predominantly (70–80%) pyramidal neurons, the principal projection neurons of the cortex. They accumulate and integrate synaptic information on their vast dendrites and pass it on locally or to other cortical and subcortical areas through excitatory synapses. Although the principal load of information transmission lies on pyramidal neurons, their activity is strongly regulated and shaped by a diverse population of local inhibitory interneurons [8.DeFelipe J. et al.Microstructure of the neocortex: comparative aspects.J. Neurocytol. 2002; 31: 299-316Crossref PubMed Scopus (480) Google Scholar]. The broad structural characteristics of pyramidal neurons are similar across species: these neurons consist of a pyramidal-shaped soma that gives rise to apical and basal dendrites. The apical dendrite is orientated towards the cortical surface and ends in a distal tuft, while basal dendrites extend radially towards deeper layers. The stereotypical organization of the cortex in a laminar structure has long tempted neuroscientists to derive generalized rules for connectivity. L1 contains mainly dendrites and axons of neurons from other layers and a sparse population of interneurons to regulate the inputs [101.Genescu I. Garel S. Being superficial: a developmental viewpoint on cortical layer 1 wiring.Curr. Opin. Neurobiol. 2021; 66: 125-134Crossref PubMed Scopus (13) Google Scholar]. Based on neuroanatomical and physiological evidence, the upper supragranular layers, L2/L3, are thought to be the place where most recurrent computation happens: L2/L3 pyramidal cells have many re-excitatory connections, preamplify information, and send it to pyramidal cells in deeper output L5/L6 [102.Shepherd G.M. The microcircuit concept applied to cortical evolution: from three-layer to six-layer cortex.Front. Neuroanat. 2011; 5: 30Crossref PubMed Scopus (76) Google Scholar]. L3 pyramidal cells are also the main source of the feedforward projections to other cortical areas and receive recurrent input from other local superficial and deep pyramidal cells. L5 pyramidal cells are part of both direct thalamocortical and cortico-cortical microcircuits and dictate output to subcortical structures [103.Takahashi N. et al.Active dendritic currents gate descending cortical outputs in perception.Nat. Neurosci. 2020; 23: 1277-1285Crossref PubMed Scopus (70) Google Scholar]. Supragranular layers seem to play an especially important role in cortico-cortical connectivity in the human brain (see Figure 2 in main text). Relative to monkeys and other primates, in humans there is a progressive shift of the laminar origin of connections from deeper (L5/L6) to upper layers (L2/L3). The result is that within human cortex a larger proportion of cortico-cortical connections originate from the supragranular layers [44.Goulas A. et al.Cortical gradients and laminar projections in mammals.Trends Neurosci. 2018; 41: 775-788Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar]. These layers are also proportionately thicker in the human cortex compared with other primates [46.Hutsler J.J. et al.Comparative analysis of cortical layering and supragranular layer enlargement in rodent carnivore and primate species.Brain Res. 2005; 1052: 71-81Crossref PubMed Scopus (98) Google Scholar], supporting a more important role of these layers in the integration of cortical information. Such gradients most likely represent increases in intracortical connectivity. In the human cortex, supragranular cortical layers, L2 and especially L3, contain large pyramidal neurons that send and receive predominantly cortico-cortical connections [44.Goulas A. et al.Cortical gradients and laminar projections in mammals.Trends Neurosci. 2018; 41: 775-788Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar,45.Semendeferi K. et al.Prefrontal cortex in humans and apes: a comparative study of area 10.Am. J. Phys. Anthropol. 2001; 114: 224-241Crossref PubMed Scopus (493) Google Scholar]. These layers are proportionally the thickest in humans (~50%) followed by other primates (46%), carnivores (36%), and then rodents (19%) [46.Hutsler J.J. et al.Comparative analysis of cortical layering and supragranular layer enlargement in rodent carnivore and primate species.Brain Res. 2005; 1052: 71-81Crossref PubMed Scopus (98) Google Scholar], suggesting distinctions between species in the proportion of cortex devoted to cortico-cortical connectivity (Figure 2). What effects do cortical expansion and increased connectivity have on the morphology of pyramidal cells? Neurons connect by making synaptic contacts on their dendrites, the larger the dendrites the more physical space for potential connections. The most distinctive feature of human pyramidal neurons compared with mouse and macaque pyramidal neurons is the size and complexity of their dendrites [19.Berg J. et al.Human neocortical expansion involves glutamatergic neuron diversification.Nature. 2021; 598: 151-158Crossref PubMed Scopus (66) Google Scholar,47.Mohan H. et al.Dendritic and axonal architecture of individual pyramidal neurons across layers of adult human neocortex.Cereb. Cortex. 2015; 25: 4839-4853Crossref PubMed Scopus (116) Google Scholar]. On average, human supragranular neurons are three times larger compared with mouse [47.Mohan H. et al.Dendritic and axonal architecture of individual pyramidal neurons across layers of adult human neocortex.Cereb. Cortex. 2015; 25: 4839-4853Crossref PubMed Scopus (116) Google Scholar] (Figure 3, Key figure). Importantly, the larger human neurons are not simp